Disubstituted-a-phenethylamines



United States Patent 9 3,346,583 N,fi-DISUBSTITUTED-a-PHENETHYLAMINESEdward D. Amstutz, Bethlehem, Pa., Frank P. Palppoli and Charles H.Tilford, Cincinnati, Ohio, and Richard F. Shuman, Allentown, Pa.,assignors to Richardson- Merrell Inc., New York, N.Y., a corporation ofDelaware No Drawing. Original application Feb. 2, 1962, Ser. No.170,828, now Patent No. 3,236,844, dated Feb. 22, 1966. Divided and thisapplication May 14, 1965, Ser. No. 463,431 r 5 Claims. (Cl. 260-296)This application is a divisional application of Ser. No. 170,828, filedFeb. 2, 1962, which has matured into Patent No. 3,236,844, granted Feb.22, 1966.

This invention relates to new chemical compounds which possess usefulphysiological properties and to a process for the preparation of thesecompounds.

The new compounds of the present invention may be regarded as basicether derivatives of -N,fl-disubstituteda-phenethylamines. They may berepresented by the formula:

in which the group represented by R is a basic ether group of theformula O(OH -Am, in which Am is a dialkylaminoor amonocyclic-nitrogen-containin-g heterov cyclic group joined to the alkylchain through a nitrogen atom. The dialkylamino groups contain alkylgroups of firom one to four carbon atoms, while the monocyclicheterocyclic groups include the morpholino, piperidino, and pyrrolid-inogroups, n is an integer from two to four. One of the radicals X and Yrepresents a heterocyclic radical and the other an aryl or substitutedaryl.

Typicalof the aryl groups that X or 'Y may rep'resent are phenyl,chlorophenyl, bromophenyl, iodophenyl, fluorophenyl,trifiuoromethylphenyl, tolyl, and met-h-oxyphenyl. Typical heterocyclicgroups that X or Y may represent are pyridyl, piperidyl and N-loweralkyl piperidyl.

This invention also includes nontoxic acid addition salts and quaternarysalts of the compounds of the general formula.

The compounds of this invention may be prepared in several ways inaccordance with the individual structural requirements. TheN,B-disubstituted-a-phenethyl-amines may be prepared by the reaction ofa suitable organometallic derivative of X or Y with an anil substitutedwith the O(CH Am group. The anil is obtained by the reaction of abasic-ether substituted benzaldehyde with an amine derivative of X or Y.

Illustrations of preparative methods are schematically represented asfollows: 7

xylene 3,346,583 Patented Oct. 10, 1967 7 R V 1 Compounds of Type I maybe catalytically hydrogenated to give the piperidine derivatives, II:

, R II The N-alkyl piperidine derivatives may be prepared in thefollowing manner:

LiAlHl GOCH:

Am-OuHZHOQ-C Ir-CH N l I R'L' Bysubstituting other acid chlorides in theabove reaction, as for example, propionyl chloride, butyryl chloride,etc., the N-propionyl and N-butyryl derivativesare obtained, which onreduction with Li-AlH give rise to the higher boiling solvent such astetrahydrofuran (B.P. 65 to 66 C.) or di-n-butylether (BP. 142 Anothermethod generally used to achieve higher reaction temperatures is thepreparation of the organometallic in the usual manner in diethyl etherand then replacing the ether with a hydrocarbon solvent such as benzene(B.P. 80 C.) or toluene (B.P. 110 C.) for the subsequent reaction of theorganometallic reagent with the anil. The reaction time here is notcritical and at the preferred temperatures the reaction is ordinarilycomplete in a short period, i.e., thirty minutes to two hours. For thesereactions preferred procedure involves the use of substantiallyequimolar quantities of the reactants, however a to excess of theorganometallic is commonly used.

After the reaction is completed the reaction mixture is decomposed bypouring onto ice, water, or a saturated ammonium chloride solution. Theorganic layer is separated, washed with water, and dried. Upon removalof the solvent the product may be isolated generally as yellowish highlyviscous oils, some of which may crystallize. Purification is effected bydistillation or chromatography on alumina.

The anils, i.e. the product of the reaction of anappropriately-substituted benzaldehyde with an appropriatelysubstitutedaniline may be prepared by variety of methods. For example, reaction maybe conveniently effected by bringing the reactants together in anon-reactive solvent such as alcohol, n-heptane, benzene, toluene, orxylene. Elevate-d temperatures such as the reflux temperature aregenerally employed to increase the reaction rate. As the reactionproceeds, water is formed, and in hydrocarbon .solvents the water may beazeotropically removed and collected in a trap. After the theoreticalamount of water is collected the reaction is considered completed. Thismay require from two to forty-eight hours. Anil formation may also beeffected merely by mixing the reactants at elevated temperature, i.e. attemperatures above room temperature. Preferably, the reaction is carriedout at temperatures in the range from about 80 to 150 C. The reactiontime here is not critical and at the preferred temperatures the reactionis ordinarily complete in a short period, i.e. minutes to two hours. Theproportion of the reactants is not critical, however a preferredprocedure involves the use of substantially equimolar quantities of thereactants. The products may be purified by distillation, or by columnchromatography on alumina.

The compounds of the present invention are potent inhibitors ofcholesterol biosynthesis. These compounds ap pear to work by a differentmechanism than triparanol and other related basic ether substitutedtriphenylethanols by inhibiting cholesterol synthesis at a differentstage in the biosynthetic pathway. These compounds are, therefore,useful in reducing the total sterol content in blood and tissues inatherosclerosis or in controlling secretion of adrenal-cortical hormonesin Cushings Syndrome. The compounds should, therefore, be useful in thetreatment of hypercholesterolemia and cardiovascular disease.

The compounds are active when administered by the oral route and may begiven in any conventional dosage form such as capsule, tablet,suspension or the like in amounts ranging from 10 mgs. to one gram perday as directed by the attending physician.

Example 1.-2-{2-( r-chloroanilino)-2-[p-(fl-diethylaminoethoxy) phenylethyl} pyridine One hundred ml. of an ether solution containing 29 g.(0.09 mole) of N-[p-(B-diethylaminoethoxy)-benzylidine]-p-chloroanilinewas added with stirring to 0.14

4 fate. The ether was removed at reduced pressure and the unreacted2-picoline distilled off by heating the dark residue at 150 C. at 1 mm.of Hg pressure. The residue was crystallized from petroleum ether togive 24.7 g. of 2-{2- (p-chloroanilin0)2-[P-. diethylaminoethoxy)phenyl]ethyl}pyridine, melting at 76 to 77 C.

The N [p (p diethylaminoethoxy)benzylidine]-pchloroaniline was preparedas follows: A mixture of 20 g. (0.0945 mole) of p (pdiethylaminoethoxy)benzalde hyde and 12.1 g. (0.0945 moles) ofp-chloroaniline were heated in 25 ml. of refluxing ethanol for 2 hours.The ethanol was removed and the residue was heated on an oil bath to240/ 0.5 mm. to remove unreacted starting material. Upon cooling, theresidue solidified to give 29.8 g. of brownish yellow product.Recrystallization from petroleum ether gave a nearly-white solid,melting at 38 to 40 C.

Example I1.Z-{2-(p-chl0r0anilin0)-2- [p-(fl-diethylaminoethoxy) phenyl]ethyl}piperidine An acetic acid solution of 2-{2-(p-chloroanilino)-2-[p-(;8diethylaminoethoxy)phenyl]ethyl}pyridine was hydrogenated, using 0.2g. of platinum oxide as catalyst and 60 pounds of hydrogen pressure.After the theoretical amount of hydrogen was absorbed, the catalyst wasremoved by filtration, the solvent evaporated and the acid saltneutralized. The desired product, 2-{2-(p-chloroanilino)-2- [p(fi-diethylaminoethoxy)phenyl]ethyl}piperidine was obtained as an oil,boiling at 144 C. at 0.2 mm. pressure.

Example III.2-{2-(p-t0luidin0)-2-[p-(fi-diethylaminoethoxy) phenyl]ethyl}pyridine The reaction of p-(B-diethylaminoethoxy)benzaldehyde andp-toluidine by the procedure of Example I gave the desired anil,N-[p-(,B-diethylaminoethoxy)benzylidine]-ptoluidine, as an oil, whichwas used without further purification. When this anil was used in placeof the anil of Example I, 2 {2(p-toluidino)-2-[p-(B-diethylaminoethoxy)phenyl]ethyl}pyridine wasobtained. The product, purified by chromatography on alumina, wasobtained as a white solid melting at 77 to 79 C.

The product of Example III, 2-{2-(p-toluidino)-2-[p-(fi-diethylaminoethoxy)phenyl]ethyl}pyridine, was hydrogenated by theprocedure of Example II to give the desired 2 {2(p-toluidino)-2-[p-(fi-diethylaminoethoxy) phenyl]ethyl}piperidine as awhite solid, melting at 785 to 79.5 C.

Example V.-2-{2-anilin0-2- [p-(B-diethylaminoethoxy) phenyl]ethyl}pyridine The reaction of p-(fi-diethylaminoethoxy)benzaldehyde andaniline by the procedure of Example I gave the desired anil,N-[p-(/8-diethylaminoethoxy)benzylidine]aniline as an oil. When thisanil was used in place of the anil of Example I, 2 {2(p-anilino)-2-[p-(;3-diethylaminoethoxy)phenyl]ethyl}pyridine wasobtained as a white solid melting at 61 to 63 C.

Example VI.2-{2- (m-chloroanilino -2- [p- (B-diethylaminoethoxy phenylethyl} pyridine The reaction of p-(B-diethylaminoethoxy)benzaldehyde andm-chloroaniline by the procedure of Example I gave the desired anil,N-[p-(B-diethylaminoethoxy)benzylidene]-m-chloroaniline, obtained as anoil. When this anil was used in place of the anil of Example I,2-{2-(mchloroanilino) 2 [p (fi-diethylaminoethoxy)phenyl] ethyl}pyridinewas obtained as a nearly white solid, melting at 62 to 64 C.

Example VIl.2-{2-(p-methoxyanilino)-2-[p-(;3-diethylaminoethoxy phenylethyl} pyridine The reaction of p-(B-diethylaminoethoxy)benzaldehyde andp-methoxyaniline by the procedure of Example I '5 gave the desiredN-[p-(fi-diethylaminoethoxy)benzylidene]-p-methoxyaniline, whichcrystallized from petroleum ether as a white solid, melting at 66 to 67C. When this anil was used in place of the anil of Example I,2-{2-(p-methoxyanilino) 2 [p-(,B-diethylaminoethoxy)phenyl]ethyl}pyridine was obtained, melting at 66 to 68 C.

Example VIII.2-{2-(p fluoroanilina)-2-[p-(,8-diethylaminoethoxy)phenyl]ethyl}pyridine The reaction ofp-(fi-diethylaminoethoxy)benzaldehyde and p-fiuoroaniline by theprocedure of Example I gave the desired anil,N-[p-(fi-diethylaminoethoxy)benzylidene]-p-fluoroaniline as an oil, B.P.182 C./0.09 mm. When this anil replaced the anil of Example I,2-{2-(pfluoroanilino) 2 [p 3 diethylaminoethoxy)phenyl] ethyl}pyridinewas obtained, melting at 53 to 56 C.

Example IX .2-{2- p-toluidino) -2- p-( fl-piperia'inoethoxy phenyl]ethyl}pyridine The reaction of p-(B-piperidinoethoxy)benzaldehyde andp-toluidine by the procedure of Example I gave the desired N[p-(B-piperidinoethoxy)benzylidene]-p-toluidene which crystallized frompetroleum ether as a solid, melting at 70 to 72 C. When this anil wasused in place of the anil of Example I, 2-{2-(p-toluidino)-2-[p-(,B-piperidinoethoxy)phenyl]ethyl}pyridine was obtained, melting at 95 to 97C.

Example X .-2-{2- p-tluidin0) -2- p- B-morpholinoethoxy )phenyl]ethyl}pyridine The reaction of p-(B-morpholinoethoxy)benzaldehyde andp-toluidine by the procedure of Example I gave the desired N-[pj8-morpholinoethoxy benzylidene] -p-t0luidine, which crystallized frompetroleum ether as a solid melting at 110 to 112 C. When this anil wasused in place of the anil of Example I, 2-{2-(p-toluidino)-2-[p- (B-morpholinoethoxy)phenyl]ethyl}pyridine was obtained, melting at 103 to105 C.

Example X I .2-{2- p-anisidino) -2- pfl-pyrrolidino'ethoxy -pheny lethyl} pyridine The reaction of p( (fi-pyrrolidinoethoxy)benzaldehydeand p-anisidine by the procedure of Example I gave the desired N [p(fi-pyrrolidinoethoxy)benzylidene] -panisidine .as a solid, melting at85 to 87 C. When this anil was used in place of the anil of Example I,2-{2-(panisidino) 2 [p-(,B-pyrrolidinoethoxy)phenyl]-ethyl} pyridine wasobtained, melting at 93 to 95 C.

Example XII .-2-{2- p-taluidino) -2- pfi-morpholins'oethaxy -phenyl]ethy l}piperidine The product of Example X, 2-{2-(p-toluidino)-2-[p-(fi-morpholinoethoxy)phenyl] ethyl}pyridine, was hydrogenated by theprocedure of Example II to give 2-{2-(ptoluidino) 2 [p(fl-morpholinoethoxy)phenyl]-ethyl} piperidine which did not crystallizeand was isolated as a pale amber, viscous oil by chromatography onalumina.

Example XIIl.2-{2-(m-trifluoromethylanilino) -2-[p-(fldiethylaminoethpxy) phenyl] ethyl} pyridine The reaction of p(,3-diethylaminoethoxy)benzaldehyde and m-trifluoromethylaniline by theprocedure of Example I gave the desired N-[p-(fi-diethylaminoethoxy)-benzylidene] -m-tri.fluoromethylaniline as an oil. When this anil wasused in place of the anil of Example I, 2-{2- (m trifluoromethylanilino)2 [p (/3 diethylaminoeth0xy)phenyl]ethyl}pyridine was obtained as a paleyellow, viscous oil, which was purified by chromatography on an aluminacolumn.

Example XlV.2-{2- (p-chloroanilino) 2- [m- (,B-diethylaminoethoxy phenylethyl} pyridine The reaction of m- B-diethylaminoethoxy) -benzaldehydeand p-chloro-aniline by the procedure of Example I gave the desiredN-[m-(fl-diethylaminoethoxy)-benzyl- -idir'1e]-p-chlor0aniline as anoil, BLP. 215' C. at 0.3

mm. When this anil was used in place of the anil of Example I, 2{2-(p-chloroanilino)-2-[m-(B-diethylaminoethoxy)phenyl] ethy1}pyridinewas obtained as an oil, BR 207 to 209 C. at 0.08. mm.

Example X V.2-{2.- p-chloroanilino -2- p- ('y-dimethyL aminopropoxyphenyl] ethyl} pyridine The reaction ofp-('y-dimethylaminopropoxy)-benzaldehyde and p-chloroaniline by theprocedure of Example I gave the desired N [p('y-dimethylaminopropoxwbenzylidene] -p-chloroaniline as a solid,melting at 62 to 64 C. When this anil was used in place 0f the anil ofExample I, 2 {2 (p-chloroanilino) 2-[p-(7-dimethylaminopropoxy)phenyl]ethyl}pyridine was obtained.

Example X VI .--2-{2-anilin0-2- p- 'y-piperidinopropoxy ph enyl ethyl}pyridine The reaction of p-(v-piperidinopropoxy) -benzaldehyde andaniline by the procedure of Example I gave the desiredN-[p-('y-piperidinopropoxy)benzylidene]-aniline as a solid, melting at49.5 to 50.5 C. When this anil was used in place of the anil of ExampleI, 2-{2-anilino-2-[p- ('y piperidinopropoxy)phenyl]ethyl}pyridine wasobtained, melting at 88 to 91 C.

Example X VII .2-{ ocpfi-di ethylaminoethoxy) phenyl]-18-phenylethylamino}pyridine The reaction of p (,3 diethylaminoethoxy)-benzaldehyde and 2-aminopyridine gave the desired anil,N-[p-(fldiethylaminoethoxy)benzylidene] 2-pyridylamine. When this anilwas allowed to react with an ether solution of benzyl magnesium chlorideas in the procedure of Example I, there was obtained2-{a-[p-(B-diethylaminoethoxy)phenyl]-fl-phenylethylamino}pyridine,melting at 75 to 76 C.

Example X VIII .-4-{2- p-ch loroanilino -2- p-( fi-di ethylaminoethoxyphenyl] ethyl} pyridine When 4-picolyl lithium replaced 2-picoly1lithium in Example I, there was obtained 4-{2-(p-chloroanilino)-2- [p(,B-diethylaminoethoxy)phenyl]ethyl}pyridine as a light amber, viscousoil, which was purified by chromatography onflan alumina column.

Example X IX .2-{2- p- ,B-diethylaminoethoxy phenyl 2- (p-toluidino)ethyl}-1-ethylpiperidine wherein Y is pyridyl and X is an 'aryl radicalof the group consisting of pheny'l, halophenyl, trifluoromet-hylphenyl,loweralkylphenyl and loweralkoxyphenyl, n is ,an integer of from 2 to 4,and Am is a radical of the group consisting of diloweralkyla-mino,morpholino, piperidino and pyrro'lidino, the nitrogen atom of saidgroups being attached to the (CH group.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,346,583 October 10, 1967 Edward D. Amstutz et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column 2, lines 50 to 60, the right-hand portion of the formula shouldappear as shown below instead of as in the patent:

column 6, lines 63 to 67, the formula should appear as shown belowinstead of as in the patent:

Am(CH O Signed and sealed this 26th day of November 1968.

(SEAL) Attest:

EDWARD J. BRENNER EDWARD M.FLETCHER,JR.

Commissioner of Patents Attesting Officer

2. 2 -(2 - (P - CHLOROANILINO) - 2-(P(B-DIETHYLAMINOETHOXY)PHENYL)ETHYL)PYRIDINE.
 3. 2 - (2 -(P-TOLUIDINO)-2-(P-(B-DIETHYLAMINOETHOXY) PHENYL)ETHYL)PYRIDINE.